title: In situ complement activation in porcine membranoproliferative glomerulonephritis type II.
abstract: Pigs genetically deficient in complement factor H all develop lethal membranoproliferative glomerulonephritis (MPGN) type II characterized by massive glomerular deposits of complement, intramembranous dense deposits, and mesangial hypercellularity. To elucidate the chronological relationship between these glomerular changes, and to precisely determine the localization of glomerular complement deposits, we studied kidney specimens from factor H-deficient piglets at different ages from fetal life until terminal kidney failure had developed. Deposits of C3 and the terminal complement complex localized within the glomerular basement membrane (GBM) were present already in factor H-deficient fetuses, without concurrent intramembranous dense deposits or mesangial hypercellularity. Incipient subendothelial dense deposits containing complement appeared no earlier than four days after birth, and intramembranous dense deposits in older piglets with established MPGN type II also contained large amounts of complement as detected by immune electron microscopy. Onset of kidney failure coincided with pronounced mesangial hypercellularity and expansion, compromising glomerular capillary patency. Formation of glomerular capillary wall double contours coincided with electron microscopic evidence of laminar disintegration of intramembranous dense deposits. Complement was also deposited in the mesangial matrix, but not on glomerular cells. We conclude that all components of the alternative and terminal pathways of complement have access into the GBM and the mesangial matrix. In the absence of factor H, complement is spontaneously activated and deposited in situ in these locations resulting in dense deposit formation. It is proposed that factor H dysfunction may play an essential role even in human MPGN type II.
authors.affiliation: Department of Morphology, Genetics and Aquatic Biology, Norwegian College of Veterinary Medicine, Oslo. Johan.H.Jansen@veths.no
authors.forename: J H
authors.initials: JH
authors.lastname: Jansen
authors.forename: K
authors.initials: K
authors.lastname: Høgåsen
authors.forename: M
authors.initials: M
authors.lastname: Harboe
authors.forename: T
authors.initials: T
authors.lastname: Hovig
mesh_terms: D000818:Animals; D001706:Biopsy; D001835:Body Weight; D003167:Complement Activation; D017242:Complement Factor H / Q000378:metabolism; D003165:Complement System Proteins / Q000032:analysis; D005260:Female; D005455:Fluorescent Antibody Technique; D015432:Glomerulonephritis, Membranoproliferative / Q000276:immunology* / Q000473:pathology*; D007678:Kidney Glomerulus / Q000276:immunology / Q000473:pathology / Q000648:ultrastructure; D008297:Male; D008854:Microscopy, Electron; D016253:Microscopy, Immunoelectron; D013552:Swine
chemical_list: C493495:CFH protein, human; D017242:Complement Factor H; D003165:Complement System Proteins